Nova ex Veteris - Novitero

10/12/2014 1 Dr. Itzchak Angel, CEO

Tailored design of new drugs that bypass resistance mutations in cancer

Nova ex Veteris

Resistance to therapies is the main cause of cancer treatment relapse

10/12/2014 Dr. Itzchak Angel, CEO 2

Tumor with heterogeneous cells

New tumor with resistant cells

Therapy Relapse

Therapy eliminates sensitive cells

People still die from cancer mainly due to the development of resistance

to therapies

Whole-body 18

F-FDG PET-CT images in 43-year old patient with DSRCT. From Ben-Sellem et al., Rare Tumors (2009)

Before treatment

Remission after treatment Relapse


Target protein

Drug fit to target

Marketed drug

To exert its therapeutic activity a drug needs to fit its target

The better the fit, the higher the affinity and activity

Mutation A Compound Mutations (A+B)

Mutation B


Structural changes (mutations) at the target recognition site cause resistance

Mutations reduce the fit of the drug to the target, rendering the drugs ineffective

I don’t fit…!

Novitero overcomes resistance through tailor-made drugs that

better fit mutated targets


Novitero redesigns marketed drugs to better fit to proteins with

multiple and compound mutations

Marketed drug

Novitero drug

Modified drug has a perfect fit to mutated target proteins

Drug redesign Fit

Emerging importance of multiple mutations

• Resistance to targeted cancer therapy and the subsequent disease propagation, treatment failure and relapse, are often caused by mutations in the target recognition site that alter the response to drugs.

• Recently, it became nonetheless evident that multiple mutations often occur, and abrogate the inhibitory action of novel third generation drugs, designed to inhibit the most frequently expressed single known mutation, to induce resistance in these targets.

• Compound mutations, defined as two or more mutations of the drug target in the same clone, may lead to enhanced resistance against the most selective inhibitors.

• The common use of sequential target-selective drugs has outlined the importance of multiple- and compound-mutations in the development of subsequent resistance to therapy

• Using ultra-deep sequencing of the BCR-ABL1 kinase domain in resistant populations, it was recently demonstrated that the frequency of multiple- and compound-mutations is much higher than previously thought.

• The need to develop drugs that will be effective against multiple- and compound-mutations is becoming evident, as the evolution of resistance to therapies persists, and the populations harboring these mutations increases.


Multiple mutations occur more frequently than

previously thought


Relative frequency of single as against compound mutants of BCR-Abl. From Soverini et al, Blood, 2013.

Novitero’s process

• Based on computational chemistry and proprietary

algorithms and processes we

– Predict and design mutated proteins

– Evaluate the impact of multiple and compound

target-mutations on drug resistance

• Design, test and develop mutation-bypassing tailored

drugs

– Broad spectrum: bypass multiple and compound

mutations

– New Patented structures


Our Process


Founder and CEO


Dr. Itzchak Angel • Experienced executive in pharmaceutical industry

•Over 30 years experience in guiding drug discovery and

development teams in both large and emerging companies

•Was previously Head of Pharmacology at Sanofi (Formerly Synthelabo,

Paris, France) and brought several drugs to market (Ambien, Xatral,

Migpriv and Mizollen)

• Formerly been VP R&D at Proteologics Ltd, D-Pharm (Rehovot, Israel)

• Head of Angel Pharmaceutical Consulting & Technologies (APCT)

Ltd

• Confirmed experience and network in business development and

pharmaceutical deals

•Co-inventor and co-author of over 100 patents and publications

Scientific Advisory Board


Prof Aaron Ciechanover, M.D, D.Sc. 2004 Nobel Prize Laureate

in Chemistry

Distinguished professor at the Tumor and Vascular Biology Research Center at The Rappaport Faculty of Medicine and Research Institute - Technion-Israel Institute of Technology

Prof. Arieh Warshel, Ph.D. 2013 Nobel Prize Laureate

in Chemistry Distinguished Professor of Chemistry and Biochemistry, Dana and David Dornsife Chair in Chemistry, Member of the Norris cancer center, University of Southern California

Targeted cancer therapy is a multi Billion $ Market.

Market size*: • Top 20 biggest-selling cancer drugs generated combined sales of $53

billion in 2013.

• Top selling small molecule targeted therapy represents a market of approximately $ 23 Billion.

• The estimated 2018 market for these drugs amounts to $ 41 Billion.

Competition: • Several drugs addressing single known mutations are under

development

• The majority of the efforts of other companies in this field are currently dedicated to the families of Iressa/Tarceva and Gleevec treatment-emergent mutations.

• Current approaches do not address combined and/or multiple mutations


* From FirstWord Pharma, March 2014 best selling cancer drug review

Major Drug

Trade name™

Company Market year

(FDA)

Target protein

Major Cancer types

Major Acquired Resistance Mutations

Imatinib Dasatinib Nilotinib Ponatinib

Gleevec Sprycel Tasigna Iclusig

Novartis BMS Novartis Ariad

2001 2006 2007 2013

BCR-ABL

GIST Leukemia NSCLC

T315I,E225K/V, Y253H,

L248R, F317V

Gefitinib Erlotinib

Iressa Tarceva

AZ/Teva Genentech

2003 2005

EGFR NSCLC

T790M, T854A

Sunitinib Sutent Pfizer 2006 RTK, KIT GIST, RCC D816H/V

Vemurafinib Dabrafenib

Zelboraf Tafinlar

Genentech GSK

2011 2013

BRAF Melanoma L505H

Vismodegib Erivedge Genentech 2012 SMO BCC D473H

Enzelutamide Xtandi Medivation 2012 AR Prostate F876L,W741C,T877A

Tofacitinib Xeljanz Pfizer 2012 JAK B-ALL E864K,G935R,Y931C

Ibrutinib Imbruvica J&J 2013 BTK BCL, Myeloma C481S

Trametinib Mekinist GSK 2013 MEK Melanoma Q60P

Crizotinib Ceritinib

Xalkori Zykadia

Pfizer Novartis

2013 2014

ALK NSCLC L1196M, G1269A, I1171T,G1202R, F1174C

Novitero can select from a large number of Targeted Therapies

Novel targeted inhibitors are effective against targets with only a single Mutations


Ponatinib (registered 2013) (Iclusig™)

Effective against T315I mutation of BCR-ABL protein

Imatinib (registered 2001) (Gleevec™, estimated 2013 sales US $ 4.7$5B)

AZD 9291 (in development, FDA breakthrough designation)

Effective against T790M mutation of EGFR protein

Erlotinib (registered 2005) (Tarceva™, estimated 2013 sales US $1.5B)

Our Business model


•Drugs are designed, tested, validated and developed for out-licensing

•Each year we design and develop several drugs

• Acting on several distinct targets

• Interfering with different cancer types

• These drugs are attractive to Pharmaceutical companies as they:

• Act on validated targets

• Are validated experimentally

• Their structure and interactions are based on marketed and

clinically proven drugs

• Have recent patents

• Their targeted and personalized design enables

• Simplified regulatory approval

• More rapid clinical development

• Well defined clinical populations and validated outcome measures


Thank you

Tailored for mutations

Nova ex Veteris*

* Nova ex Veteris – From Latin, “The new is created from the old”

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